Association between metabolic syndrome and venous thromboembolism after total joint arthroplasty: a meta-analysis of cohort studies

Objective Metabolic syndrome (MetS) has been associated with hypercoagulative status. However, previous studies evaluating the association between MetS and incidence of venous thromboembolism (VTE) after total joint arthroplasty (TJA) showed inconsistent results. We performed a meta-analysis to evaluate the influence of MetS on the risk of VTE following TJA. Methods Cohort studies were identified by the search of PubMed, Embase, and the Cochrane’s Library databases. A random-effect model was used if considerable heterogeneity was detected; otherwise, a fixed-effect model was used. Subgroup analyses according to the category of VTE, definition of MetS, category of procedure, and follow-up durations were performed. Results Seven cohort studies with 1,341,457 patients that underwent TJA were included, with 118,060 MetS patients (8.8%) at baseline. With a follow-up duration up to 3 months after surgery, 9788 patients had VTE. Pooled results with a random-effect model showed that MetS was not associated with increased overall VTE after TJA (adjusted risk ratio [RR] = 1.24, 95% confidence interval [CI] 0.89 ~ 1.72, p = 0.20; I2 = 69%). The results were not significantly affected by the diagnostic criteria of MetS, category of the procedure, and follow-up durations. Subgroup analyses showed that MetS was not associated with an increased the risk of pulmonary embolism ([PE], RR 1.06, 95% CI 0.37 ~ 3.02, p = 0.91), but an increased risk of deep vein thrombosis (DVT) after TJA (RR 3.38, 95% CI 1.83 ~ 6.24, p < 0.001). Conclusions Current evidence from observational studies suggests MetS might be associated with an increased risk of DVT but not PE after TJA.


Introduction
Patients undergoing total joint arthroplasty (TJA), including total knee arthroplasty (TKA) and total hip arthroplasty (THA), are at a higher risk for the development of venous thromboembolism (VTE) [1][2][3]. Despite the routine use of prophylactic measures against thrombosis in these patients, the incidences of VTE, including pulmonary embolism (PE) and deep vein thrombosis (DVT) remains high [4]. A previous systematic review including 44,844 cases from 47 studies showed that in patients receiving recommended prophylaxis, the pooled rates of symptomatic postoperative VTE before hospital discharge were 1.09% for patients undergoing TKA and 0.53% for those undergoing THA [5]. Moreover, VTE has become an important cause of morbidity and mortality in patients after TJA [6]. Identification of risk factors for VTE in patients that received TJA is clinically important [6].
Metabolic syndrome (MetS) refers to a cluster of metabolic abnormalities including abdominal adiposity, insulin resistance, hyperglycemia, hypertension, and dyslipidemia [7,8]. Accumulating evidence suggests that patients MetS are characterized by hypercoagulative status [9][10][11][12][13]. Indeed, MetS has been associated with a 2-fold increase in arterial thrombotic diseases, such as coronary artery disease and stroke [14]. Moreover, a previous individual-patient data-based meta-analysis showed that MetS is associated with an increased risk of unprovoked VTE in general population [15]. Since MetS is prevalent in patients undergoing TJA, accumulating studies have evaluated the association between MetS and risk of VTE in these patients [16][17][18][19][20][21][22]. However, the results of these studies are inconsistent. Some of them suggested that MetS may be a risk factor for VTE after TJA [16,19,21], while other studies did not [17,18,20,22]. Therefore, we aimed to perform a meta-analysis to evaluate the association between MetS and risk of VTE in patients after TJA. The influences of categories of VTE, definitions of MetS, and types of procedures on the association were also analyzed.

Methods
The meta-analysis was designed and performed in accordance with the MOOSE (Meta-analysis of Observational Studies in Epidemiology) [23] and Cochrane's Handbook [24] guidelines.

Literature search
Electronic databases of PubMed, Embase, and the Cochrane's Library were systematically searched using the combination of the following terms: [1] "metabolic syndrome" OR "insulin resistance syndrome" OR "syndrome X" [2]; "hip" OR "knee"; and [3] "arthroplasty" OR "replacement" OR "surgery" OR "operation". We used this extensive search strategy to avoid missing potential studies. The search was limited to human studies published in English or Chinese. The reference lists of original and review articles were also analyzed manually. The final literature search was performed on April 2, 2020.

Study selection
Studies were included if they met the following criteria: [1] published as full-length article, [2] designed as cohort studies, [3] included patients that received TKA or THA, [4] MetS was identified as exposure of interest at baseline, [5] documented the incidence of any VTE events (overall VTE, PE, or DVT) in patients with and without MetS, and [6] reported the adjusted risk ratios (RRs, at least adjusted for age and sex) and their corresponding 95% confidence intervals (CIs) for the incidence of VTE in patients with and without MetS. Definitions of MetS were consistent with what was applied in the original studies. Reviews, editorials, preclinical studies, and non-cohort studies were excluded.

Data extracting and quality evaluation
Literature search, data extraction, and study quality assessment were independently performed by two authors according to the predefined inclusion criteria. If inconsistencies occurred, discussion with the corresponding author was suggested to resolve the disagreement. The following data were extracted: [1] name of the first author, publication year, study location, and study design [2]; characteristics and numbers of patients that received TKA or THA, criteria for the diagnosis of MetS, prevalence of MetS, and follow-up period; and [3] number of cases with any VTE events during follow-up, VTE prophylactic strategies, methods for the validation of the outcome, and variables adjusted. The quality of each study was evaluated using the Newcastle-Ottawa Scale (NOS) [25]. This scale ranges from 1 to 9 stars and judges the quality of each study regarding three aspects: the selection of the study groups, the comparability of the groups, and the ascertainment of the outcome of interest.

Statistical analyses
The association between MetS and VTE in patients after TKA or THA was measured by RRs. To stabilize its variance and normalized the distribution, RR data and its corresponding stand error (SE) from each study was logarithmically transformed [24]. The Cochrane's Q test was performed to evaluate the heterogeneity among the include cohort studies [24,26], and the I 2 statistic was also calculated. A significant heterogeneity was considered if I 2 > 50%. A random effect model was used to pool the results if significant heterogeneity was detected; otherwise, a fixed-effect model was used. Sensitivity analysis by omitting one study at a time was performed to evaluate the stability of the results [24]. To evaluate the influences of categories of VTE, definitions of MetS, types of procedures, and follow-up durations on the association, subgroup analyses were performed. Potential publication bias was assessed by visual inspection of the symmetry of the funnel plots, complemented with the Egger regression test [27]. P < 0.05 was considered as statistically significant. The RevMan (Version 5.1; Cochrane Collaboration, Oxford, UK) and STATA software were used for the statistics.

Literature search
The flowchart of the database search was shown in Fig. 1. Briefly, 788 studies were obtained from the database search, and 768 of them were excluded primarily due to the irrelevance to the purpose of the study. For the remaining 20 potential relevant studies that underwent full-text review, 13 were further excluded for the reasons listed in Fig. 1. Finally, seven cohort studies were included [16][17][18][19][20][21][22].

Study characteristics and quality
Characteristics of the included studies were summarized in Table 1. Overall, seven cohort studies with 1,341,457 patients that underwent TJA were included [16][17][18][19][20][21][22]. These studies were performed in the USA, Canada, and China and published between 2009 and 2018. One of them was a prospective cohort study [16], and the others were retrospective cohorts [17][18][19][20][21][22]. Since two studies reported the incidence of VTE events in patients received TKA and THA separately, these datasets were independently included. Therefore, nine datasets were available for the meta-analysis, and 118,060 patients (8.8%) were diagnosed as MetS at baseline according to the World Health Organization (WHO) [16,20,21] or the National Cholesterol Education Program Expert Panel and Adult Treatment Panel III (NCEP-ATP III) criteria [17][18][19]22]. The follow-up duration varied between within hospitalization and 3 months after surgeries, and 9788 patients had VTE during follow-up. Strategies for VTE prophylaxis were reported in three studies [16,19,21], and anticoagulants of warfarin, rivaroxaban, or low-molecularweight heparin were used. The methods for VTE assessment were also reported in three studies [16,19,21], which involved the application of Doppler ultrasonography, venography, and CT and/or lung VQ scan. Potential confounding factors, including age, sex, body mass index (BMI), smoking, and comorbidities, were adjusted to a varying degree in the included studies. The qualities of the included follow-up studies were generally good, with the NOS ranging from 68 ( Table 2).

Association between MetS and VTE after TJA
Significant heterogeneity was detected among the studies that evaluated the association between MetS and VTE   Fig. 4) after JTA.

Publication bias
The funnel plots for the association between MetS and VTE after TKA or THA were shown in Fig. 5. The plots were symmetrical on visual inspection, suggesting low risks of publication biases. Results of Egger's regression tests also showed similar results (p = 0.389).

Discussion
In this meta-analysis of cohort study, we found that MetS at baseline was not associated with an increased risk of overall VTE events in patients after TJA. Subgroup analysis showed that MetS was independently associated with an increased risk of DVT, but not PE in patients after TJA. Moreover, the results were not significantly affected by the diagnostic criteria of MetS, the types of surgical procedures, and the follow-up durations. Taken together, current evidence from observational studies suggests that MetS might be associated with an increased risk of DVT, but not PE in patients after TJA.
To the best of our knowledge, our study is the first meta-analysis to evaluate the potential association between MetS and VTE risk in patients after TJA. Although we did not show that MetS was independently This Newcastle-Ottawa Scale ranges from 1 to 9 stars and judges the quality of each study regarding the nine domains as listed in the table, with higher scores indicating better study quality associated with an increased incidence of overall VTE, subgroup analysis suggests that MetS was associated with an increased risk of DVT but not PE in these patients. The potential reasons for the findings remain unknown. Generally, PE was resulted by thrombi from the lower extremities of patients with DVT. Due to the routine use of prophylactic measures against VTE in patients after TJA, the incidence of PE in these patients is lower than the incidence of DVT [28]. In our study, the pooled incidence of DVT was 4.7% and compared to 1.6% for PE. It could be hypothesized that potential differences in patient characteristics or diagnostic strategies may be responsible for the observed different associations between MetS with DVT and PE. However, limited datasets included in the subgroup analysis prevented further analysis. Moreover, we found that the results were not significantly affected by the diagnostic criteria of MetS or the types of surgical procedures. Previous studies showed that patients after TKA seem to have a higher incidence of VTE events than those after THA [5,28]. Although the overall meta-analysis did not show a significant association between MetS and VTE after TJA, subgroup analysis suggested that MetS was associated with increased DVT after TJA. Since only three datasets were included in the subgroup analysis of DVT events,   [29], and the VTE events occurred were mainly DVT. These findings may suggest the importance of MetS control for the reducing the risk of DVT after TJA. The potential pathophysiological mechanisms underlying the association between MetS and increased risk of DVT after TJA may be multifactorial. Patients with MetS are characterized by a persistent activated chronic inflammatory response. Since inflammation is a major activator of coagulation, these patients are generally at hypercoagulative status, thereby vulnerable to venous thrombosis [10,11]. Moreover, it has been shown that patients with MetS have impaired spontaneous thrombolytic activity as reflected by an impaired expression of tissue-type plasminogen activator [30], which may also be involved in their vulnerability to thrombotic events. Besides, patients with MetS tend to be overnutrition and are more likely to be exposed to high-fat diet. Previous studies showed that high-fat diet maintains high endogenous thrombin potential, which is associated with venous and arterial thrombosis independently of obesity and insulin resistance [31]. However, the correlation of nutritional status and VTE risk could be complex, since recent studies showed that the poor nutrition status was also associated with a high risk of developing DVT, particularly for those who underwent major surgeries [32,33]. Further studies are needed to elucidate the mechanisms underlying the association between MetS and DVT.
Our study has limitations, which should be considered when interpreting the results. Firstly, as a meta-analysis of observational studies, although we combined RR data after adjustment of potential confounding factors, we  could not exclude other residual factors that may confound the association between MetS and DVT after TJA, such as the comorbidities of the patients and concurrent medications [34]. Secondly, due to the limited number of the included studies, the result of the subgroup analysis should be interpreted with caution. In addition, most of the included studies were retrospective, which may be limited by the recall bias compared to prospective studies. Moreover, the lengths of follow-up varied among the included studies. However, subgroup analysis showed that MetS was not associated with increased VTE risk after TJA in studies of follow-up within hospitalization, 1 month, and 3 months after JTA. Besides, the long-term (> 3 months) association between MetS and VTE risk after TJA remains to be determined in future studies. Finally, a causative relationship between MetS and increased DVT after TJA should not be retrieved from our results since it is a meta-analysis of observational studies.

Conclusions
In conclusion, our meta-analysis showed that current evidence from observational studies suggests MetS might increase the risk of DVT but not PE in patients that received TJA. Although these findings should be validated in prospective studies, the results of this meta-analysis may suggest the importance of MetS control for reducing the risk of DVT after TJA.